Abstract
BackgroundOne of the hallmarks of cancer is the occurrence of high levels of chromosomal rearrangements as a result of inaccurate repair of double-strand breaks (DSB). Germline mutations in BRCA and RAD51 genes, involved in DSB repair, are strongly associated with hereditary breast cancer. Pol θ, a translesional DNA polymerase specialized in the replication of damaged DNA, has been also shown to contribute to DNA synthesis associated to DSB repair. It is noteworthy that POLQ is highly expressed in breast tumors and this expression is able to predict patient outcome. The objective of this study was to analyze genetic variants related to POLQ as new population biomarkers of risk in hereditary (HBC) and sporadic (SBC) breast cancer.MethodsWe analyzed through case–control study nine SNPs of POLQ in hereditary (HBC) and sporadic (SBC) breast cancer patients using Taqman Real Time PCR assays. Polymorphisms were systematically identified through the NCBI database and are located within exons or promoter regions. We recruited 204 breast cancer patients (101 SBC and 103 HBC) and 212 unaffected controls residing in Southern Brazil.ResultsThe rs581553 SNP located in the promoter region was strongly associated with HBC (c.-1060A > G; HBC GG = 15, Control TT = 8; OR = 5.67, CI95% = 2.26-14.20; p < 0.0001). Interestingly, 11 of 15 homozygotes for this polymorphism fulfilled criteria for Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Furthermore, 12 of them developed bilateral breast cancer and one had a familial history of bilateral breast cancer. This polymorphism was also associated with bilateral breast cancer in 67 patients (OR = 9.86, CI95% = 3.81-25.54). There was no statistically significant difference of age at breast cancer diagnosis between SNP carriers and non-carriers.ConclusionsConsidering that Pol θ is involved in DBS repair, our results suggest that this polymorphism may contribute to the etiology of HBC, particularly in patients with bilateral breast cancer.
Highlights
One of the hallmarks of cancer is the occurrence of high levels of chromosomal rearrangements as a result of inaccurate repair of double-strand breaks (DSB)
The allelic distribution for the other polymorphisms were in Hardy-Weinberg equilibrium in all groups, and the observed allele frequencies in controls are in agreement with those described for euro-descendants in the 1000 Genomes database
The POLQ genotype frequencies were distributed in Sporadic Breast Cancer (SBC) and controls with the exception of rs581553 located in the promoter region of the gene, which was strongly associated with an increased risk for Hereditary Breast Cancer (HBC)
Summary
One of the hallmarks of cancer is the occurrence of high levels of chromosomal rearrangements as a result of inaccurate repair of double-strand breaks (DSB). Germline mutations in BRCA and RAD51 genes, involved in DSB repair, are strongly associated with hereditary breast cancer. Among the established risk factors for breast cancer are germline mutations in two highly penetrant genes: BRCA1 and BRCA2 [1,2]. These mutations strongly increase breast cancer risk by disrupting homologous recombination repair (HRR) of DNA double strand breaks (DSBs) [3,4]. Mutations in the BRCA genes and other genes encoding proteins involved in DSB repair (i.e. RAD51) are mostly associated with hereditary breast cancer and increase the genetic instability caused by DSBs [6,7,8]
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